Common pathophysiology of fibrotic CTD-ILDs

While CTDs differ, common pathogenic pathways to fibrogenesis are shared irrespective of the trigger for the lung injury1–4

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Learn about the pathophysiological mechanisms behind inflammation and fibrosis that are common across a broad range of CTD-ILDs



The pathogenesis of fibrotic interstitial lung disease in connective tissue diseases involves a complex interplay of inflammatory and fibrotic processes. Patients with connective tissue diseases (CTDs), such as rheumatoid arthritis, systemic sclerosis and primary Sjogren’s syndrome, develop fibrotic interstitial lung disease (ILD) via common pathogenic processes, irrespective of the underlying diagnosis or trigger. Fibrotic ILD often develops early in the course of a CTD. For example, in a study of systemic sclerosis patients, approximately 24% of systemic sclerosis-associated ILD patients showed an extent of more than 10% pulmonary fibrosis on high-resolution computed tomography at their baseline systemic sclerosis diagnosis. At the cellular level, ILD in CTDs is triggered by repeated tissue injury which induces an inflammatory response, and releases probiotic mediators, including VEGF, PDGF and FGF. These contribute to the recruitment and activation of leukocytes and fibroblasts. Resulting in a complex interplay of inflammatory and fibrotic processes. Activation of leukocytes also produces profibrotic mediators leading to further activation of the fibrotic process with excessive secretion of extracellular matrix. Excess extracellular matrix increases lung tissue stiffness, further activating fibroblasts in a feed-forward loop of self-sustaining progressive pulmonary fibrosis. Pulmonary fibrosis causes irreversible destruction and architectural disruption of the lung tissue. Based on the pathogenesis of fibrotic interstitial lung disease in connective tissue diseases, a new treatment paradigm of CTD-ILDs suggests to not only target inflammation but also fibrosis.

While ILDs differ, common pathogenic pathways to fibrogenesis are shared1,2.4,8,9

Pathogenic pathways of fibrogenesis in CTD-ILDs

A complex interplay of inflammatory, fibrotic and vascular processes leads to the activation and proliferation of fibroblasts, their differentiation into myofibroblasts, and the excessive secretion of extracellular matrix5,6,10

Learn more about the interplay of inflammation and fibrosis in fibrotic CTD-ILDs


Irrespective of the clinical diagnosis, there are commonalities in the underlying pathogenetic mechanisms that drive a self-sustaining process of pulmonary fibrosis4

Once pulmonary fibrosis has become self-sustaining, fibroblasts can become partially independent of external stimulation and the initiating inflammatory response11,12

Self-sustaining progression of fibrosis5,13,14


Progressive fibrosing CTD-ILDs are driven by a common pathophysiology12 – ensure you are targeting key pathways leading to fibrosis in your patients with CTD-ILDs

How can you screen and diagnose fibrotic ILD early in your patients with CTDs?

  • CTD, connective tissue disease; CTD-ILD, connective tissue disease-associated interstitial lung disease; HRCT, high-resolution computed tomography; ILD, interstitial lung disease.

  1. Cottin V, Hirani N, Hotchkin D, et al. Presentation, diagnosis and clinical course of the spectrum of progressive-fibrosing interstitial lung diseases. Eur Respir Rev. 2018;27(150):180076.

  2. Wuyts WA, Agostini C, Antoniou KM, et al. The pathogenesis of pulmonary fibrosis: a moving target. Eur Respir J. 2013;41(5):1207–1218.

  3. Maher TM, Wuyts W. Management of fibrosing interstitial lung diseases. Adv Ther. 2019;36(7):1518–1531.

  4. Kolb M, Vašáková M. The natural history of progressive fibrosing interstitial lung diseases. Respir Res. 2019;20(1).

  5. Wells AU, Denton CP. Interstitial lung disease in connective tissue disease— mechanisms and management. Nat Rev Rheumatol. 2014;10:728–739.

  6. Castelino FV and Varga J. Interstitial lung disease in connective tissue diseases: evolving concepts of pathogenesis and management. Arthritis Res Ther. 2010;12(4):213. doi: 10.1186/ar3097.

  7. Dellaripa PF. Interstitial lung disease in the connective tissue diseases; a paradigm shift in diagnosis and treatment. Clin Immunol. 2018;186:71–73.

  8. Selman M, King TE, Pardo A, et al. Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med. 2001;134(2):136–151.

  9. Bagnato G and Harari S. Cellular interactions in the pathogenesis of interstitial lung diseases. Eur Respir Rev. 2015;24(135):102–114.

  10. Fischer A and Distler J. Progressive fibrosing interstitial lung disease associated with systemic autoimmune diseases. Clin Rheumatol. 2019;38(10):2673–2681.

  11. Distler J, et al. Shared and distinct mechanisms of fibrosis. Nat Rev Rheumatol 2019(b):15:705–30.

  12. Kolb M, Flaherty KR. The justification for the progressive fibrotic phenotype. Curr Opin Pulm Med 2021; online ahead of print.

  13. Saketkoo LA, Scholand MB, Lammi MR, et al. Patient-reported outcome measures in systemic sclerosis–related interstitial lung disease for clinical practice and clinical trials. Scleroderma Relat Disord. 2020;5(2 Suppl): 48–60.

  14. Wollin L, Distler JHW, Redente EF, et al. Potential of nintedanib in treatment of progressive fibrosing interstitial lung diseases. Eur Respir J. 2019;54(3):1900161. doi: 10.1183/13993003.00161-2019.

  15. Brauner M, et al. Imagerie des pneumopathies infiltrantes diffuses. Press Med. 2010;39:73–84.

  16. Geerts S, Wuyts W, De Langhe E, et al. Connective tissue disease associated interstitial pneumonia: a challenge for both rheumatologists and pulmonologists. Sarcoidosis Vasc Diffuse Lung Dis. 2017;34(4):326–335.

  17. Wallace B, Vummidi D, Khanna D. Management of connective tissue diseases associated interstitial lung disease: a review of the published literature. Curr Opin Rheumatol. 2016;28(3):236–245.

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